Conventional thiopurines are considered to be effective and safe in the treatment of inflammatory bowel disease (IBD) patients; unfortunately more than 50% of patients discontinue thiopurine therapy, mainly due to the development of intractable adverse events. In recent years, the use of 6-thioguanine has been proposed as an alternative thiopurine in IBD patients failing to tolerate or to respond to conventional thiopurine therapy. In this clinical review, we describe the rationale for 6-thioguanine therapy and discuss the reported hepatotoxicity of 6-thioguanine (especially nodular regenerative hyperplasia). We propose expert-based guidelines for balanced treatment.